This project studies novel mechanisms by which dietary factors, using soy protein isolate as the nutritional paradigm, inhibit colon cancers of the rat and mouse (and by inference human). The Central Hypothesis under study posits that dietary soy protein isolate reduces circulating insulin levels and as a consequence, colonic expression of lipogenic enzymes, which in turn confers reduced proliferation and increased apoptosis during colon tumor initiation and progression. Sprague-Dawley rats will be fed high fat diets to induce obesity and hyperinsulinemia. Diets will contain equal amounts of casein (control protein) or soy protein isolate (SPI). These dietary proteins elicited significant differences in intestinal tumor indices after administration of the chemical carcinogen, azoxymethane (AOM). SPI suppressed: a) numbers of aberrant crypt foci (ACF; intermediate end-point biomarker of colon adenomas/carcinomas), b) incidence of colon tumors, c) systemic insulin levels, and d) expression of lipogenic enzyme genes in colon (both prior to and during tumorigenesis). Soy protein, when fed only during pregnancy, influenced the outcome of AOM-induced tumorigenesis in the progeny as later adults (nutritional programming of colon cancer). Thus, there is support for linkages of dietary protein type, metabolic regulation of lipid synthetic enzyme genes, and colon cancer. Three Specific Aims will examine these proposed linkages by elucidating the inhibitory actions of dietary SPI on initiation of colon tumorigenesis in the high fat-fed, obese rat; examining the inhibitory actions of dietary SPI on colon tumor progression in the high fat-fed rat and mouse; and investigating mechanisms of obesity-induced fetal programming of colon tumorigenesis. Emphasis in all three Aims will be on lipogenic enzyme genes as downstream pro-proliferative and anti-apoptotic targets of insulin and thyroxine, in obese states. Long-term goals are to utilize proteins/peptides and non-protein bio-active factors present in soy protein isolates, and the targeting of downstream lipogenic enzyme genes/pathways, to augment human colo-rectal cancer- and obesity-prevention strategies. These studies have strong translational significance for improving the health and quality of life of the overweight/obese population at risk for or afflicted with colo-rectal cancer.